Claims:

1. A process for preparing anhydrous aripiprazole Type I comprising:(A)
dissolving aripiprazole, or an acid salt thereof, in a water miscible
organic solvent, optionally containing up to 50% water (by volume), with
heating to form a solution of aripiprazole, or a solution of an acid salt
thereof;(B) when the solution comprises a solution of an acid salt,
adding a base to the solution in an amount sufficient to neutralize the
acid salt;(C) optionally contacting the solution with decolorizing carbon
or diatomaceous earth;(D) while maintaining the temperature of the
solution above about 70.degree. C., add sufficient water to produce an
aqueous organic solution containing at least 5% water (by volume);(E)
cooling the aqueous organic solution, as required, to a temperature of 25
to 78.degree. C. and seeding the solution with anhydrous aripiprazole
Type I crystals;(F) agitating the aqueous organic solution at a
temperature in the range of 25 to 78.degree. C. to initiate
crystallization and form a slurry containing aripiprazole crystals;(G)
cooling the aripiprazole slurry with agitation to a temperature in the
range of 15 to 25.degree. C., and maintaining the slurry in that
temperature range for at least 2 hours to complete crystal formation;(H)
isolating the crystals by filtration and optionally washing the crystals
with organic solvent; and(I) drying the isolated crystals under a vacuum
and at a temperature of not greater than 80.degree. C. until the isolated
crystals contain less than about 1.0% water by weight.

2. The process according to claim 1, wherein the water miscible organic
solvent optionally contains up to 30% water (by volume), the aqueous
organic solution is cooled, as required, to a temperature of 45 to
78.degree. C. in step (E) and the aqueous organic solution is agitated at
a temperature in the range of 45 to 60.degree. C. in step (F).

3. The process according to claim 2, wherein the organic solvent comprises
an alcoholic solvent selected from the group consisting of methanol,
ethanol, isopropanol, n-butanol and pentanol.

4. The process according to claim 3, wherein the alcoholic solvent
comprises isopropanol.

5. The process according to claim 2, wherein the aqueous organic solution
contains about 5 to about 30 percent water (by volume).

6. The process according to claim 5, wherein the aqueous organic solution
contains about 15 to about 25 percent water (by volume).

7. The process according to claim 2, wherein seeding is carried out at a
temperature in the range of about 45 to 60.degree. C.

8. The process according to claim 7, wherein seeding comprises adding
anhydrous aripiprazole Type 1 crystals in an amount of about 0.05 to
about 1.0 percent by weight of the original aripiprazole.

9. The process according to claim 8, wherein seeding comprises adding
aripiprazole hydrate crystals in an amount of about 0.1% by weight of the
original aripiprazole.

[0002]Aripiprazole is an atypical antipsychotic agent useful for the
treatment of schizophrenia. Schizophrenia is a common type of psychosis
characterized by delusions, hallucinations and extensive withdrawal from
others. Onset of schizophrenia typically occurs between the age of 16 and
25 and affects 1 in 100 individuals worldwide. It is more prevalent than
Alzheimer's disease, multiple sclerosis, insulin-dependent diabetes and
muscular dystrophy. Early diagnosis and treatment can lead to
significantly improved recovery and outcome. Moreover, early therapeutic
intervention may avert costly hospitalization.

[0003]U.S. Pat. No. 4,734,416 and U.S. Pat. No. 5,006,528, both assigned
to Otsuka, describe aripiprazole and processes for its preparation. These
patents also disclose various salts of aripiprazole and their
preparation. Preparation of conventional anhydrous aripiprazole Type 1
also was disclosed in Fourth Japanese-Korean Symposium on Separation
Technology (Oct. 6-8, 1996). According to the Proceedings of the 4th
Japanese-Korean Symposium on Separation Technology, aripiprazole
anhydride crystals are manufactured by heating, at 80° C.,
aripiprazole hydrate previously re-crystallized from an aqueous ethanol
solution.

[0004]WO 03/026659 (corresponding to U.S. Publication 2004/0058935) also
teaches a method of preparing a conventional hydrate of aripiprazole
hydrate in which crude aripiprazole crystals are dissolved in a hydrous
organic solvent, the solution is heated and then cooled. As described,
the organic solvent is one which is miscible with water, such as for
example an alcohol, acetone, an ether and their mixtures. Ethanol is
apparently preferred. The amount of water in the hydrous solvent can be
10-25% by volume of the solvent, or preferably close to 20% by volume.

[0005]US Patent Publication 2005/0277650 alleges that the aripiprazole
hydrate prepared as per WO 03/026659 does not provide consistent results
and that by an altered process conventional aripiprazole hydrate can be
prepared with more consistent results.

[0006]In particular, US Patent Publication 2005/0277650 describes a
process for preparing aripiprazole hydrate in which aripiprazole is
dissolved in an aqueous, organic solvent; the solution is heated to a
temperature of above about 67° C.; the heated solution is seeded
with aripiprazole hydrate crystals at a temperature of above about
67° C.; the so-seeded solution is cooled to a temperature in the
range of about 50° C. to about 55° C. and is maintained at
that temperature as crystals form; followed by further cooling of the
solution to a temperature in the range of about 0° C. to about
10° C. and maintaining such temperature as crystals form;
separating the crystals from the cooled solution; and drying the
separated crystals at a temperature of about 45° C. to about
50° C. until the water content of the dried crystals is about 3 to
about 4.5 percent by weight.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007]FIG. 1 is an X-ray powder diffractogram (XRD) of the anhydrous
aripiprazole crystal obtained on the final sample of Batch 1 dried for 40
hours in a 60 to 65° C. as described in the Example.

[0008]FIG. 2 is an X-ray powder diffractogram (XRD) of the anhydrous
aripiprazole crystal obtained on the final sample of Batch 2 dried for 40
hours in a 60 to 65° C. as described in the Example.

[0009]FIG. 3 is an X-ray powder diffractogram (XRD) of the anhydrous
aripiprazole crystal obtained on the final sample of Batch 3 dried for 40
hours in a 60 to 65° C. as described in the Example.

[0010]FIG. 4 is an X-ray powder diffractogram (XRD) of the anhydrous
aripiprazole crystal obtained on the final sample of Batch 1 dried for 40
hours in a 70 to 80° C. as described in the Example.

[0011]FIG. 5 is an X-ray powder diffractogram (XRD) of the anhydrous
aripiprazole crystal obtained on the final sample of Batch 2 dried for 40
hours in a 70 to 80° C. as described in the Example.

[0012]FIG. 6 is an X-ray powder diffractogram (XRD) of the anhydrous
aripiprazole crystal obtained on the final sample of Batch 3 dried for 40
hours in a 70 to 80° C. as described in the Example.

DETAILED DESCRIPTION OF THE INVENTION

[0013]The inventors of the present invention have discovered that using
conventional, anhydrous Type I crystals to seed an aqueous organic
solution of aripiprazole that additional anhydrous Aripiprazole Type I
crystals can be obtained in a consistent manner.

[0014]Thus, the present invention provides an improved process for the
preparation of conventional anhydrous aripiprazole Type I crystals.

[0015]In one embodiment, an improved process for the preparation of
anhydrous aripiprazole Type I comprises:

(A) dissolving aripiprazole, or an acid salt thereof, in a water miscible
organic solvent (preferably an alcoholic solvent), optionally containing
up to 50% water (by volume), and usually up to 30% water (by volume),
with heating to form a solution of aripiprazole, or an acid salt
thereof;(B) when the solution comprises an acid salt, adding a base to
the solution in an amount sufficient to neutralize the acid salt;(C)
optionally contacting the solution with decolorizing carbon or
diatomaceous earth;(D) while maintaining the temperature of the solution
above about 70° C., adding sufficient water to produce an aqueous
organic solution containing at least 5% water (by volume);(E) cooling the
aqueous organic solution, as required, to a temperature of 25 to
78° C., usually to a temperature of 45 to 78° C., and
seeding the solution with anhydrous aripiprazole Type I crystals;(F)
agitating the aqueous organic solution at a temperature in the range of
25 to 78° C., usually at a temperature in the range of 45 to
60° C., to initiate crystallization and form a slurry containing
aripiprazole crystals;(G) cooling the aripiprazole slurry with agitation
to a temperature in the range of 15 to 25° C., and maintaining the
slurry in that temperature range for at least 2 hours to complete crystal
formation;(H) isolating the crystals by filtration and optionally washing
the crystals with organic solvent; and(I) drying the isolated crystals
under a vacuum and at a temperature of not greater than 80° C.
until the isolated crystals contain less than about 1.0% water by weight.

[0016]The water miscible organic solvents that can be used for preparing
the anhydrous aripiprazole include alcohols such as methanol, ethanol,
isopropanol, n-butanol and pentanol, acetic acid, tetrahydrofuran,
acetonitrile and mixtures thereof. Preferably, an alcoholic solvent is
used and especially isopropanol (isopropyl alcohol) is used.

[0017]The hydrous organic solvent contains from 5 to 50% water by volume,
usually 5 to 30% water, more usually 15 to 25% water, and most often
about 20% water by volume.

[0018]Seeding the aqueous organic solution comprises adding anhydrous
aripiprazole Type I crystals, typically in an amount about 0.05% to 1.0%
by weight of the dissolved aripiprazole, and usually in an amount of
about 0.1% by weight. The seeding crystals are added to the cooled
aqueous alcoholic solution at a temperature in the range of 25 to
78° C., usually the cooled aqueous alcoholic solution is at a
temperature in the range of 45 to 78° C.

[0019]The isolated crystals are preferably dried to a moisture content of
less than 0.5%, more usually less that 0.1% and often to a moisture
content of less that 0.05%. The isolated crystals are generally dried for
a period of time that varies inversely with the temperature. Preferably,
the isolated crystals are dried at a temperature in the range of 60 to
70° C., for a period of up to 40 hours. Usually, the drying is
accompanied by a vacuum assist.

[0020]The process of the present invention constitutes a simple and
industrially scaleable process that is pharmaceutically acceptable for
the consistent synthesis of anhydrous Type I aripiprazole.

[0021]A specific embodiment of the process of the present invention is
illustrated in more detail with reference to the following example, which
is provided by way of illustration only and should not be construed as a
limit on the scope of the appended claims.

EXAMPLE

Preparation of Anhydrous Aripiprazole Type 1

[0022]Crude aripiprazole, or an acid salt thereof, can be prepared in any
convenient manner. In this example, the source of the aripiprazole is a
wet, crude aripiprazole HCl salt.

[0023]The aripiprazole HCl (794.5 parts by weight (ppw)), is refluxed in
isopropanol (1089.9 ppw) to remove, by distillation, any residual
synthesis solvents, and then cooled to terminate reflux conditions.
Sodium hydroxide (22.1 ppw of a 50% by weight aqueous solution) is added
and stirred for 30 minutes at a temperature of 75-80° C. to
neutralize the HCl salt. The pH of a 2 ml sample of the resulting slurry
in 10 ml of water should measure not less than 12 (add additional sodium
hydroxide as needed to raise the pH to not less than 12). The hot
solution then is filtered in contact with either decolorizing carbon or a
diatomaceous earth (13 ppw) as an absorbent. The solids, salts and
absorbent, are discarded. Keeping the filtrate at a temperature above
70° C., such as between 75-80° C., water is added in an
amount (140 ppw) sufficient to provide an aqueous solution of isopropanol
containing about 20% by volume water. Then, the solution is cooled to
about 60° C. and anhydrous aripiprazole Type I crystals (0.07 ppw)
are added and the solution is agitated. Crystallization is initiated by
agitating the seeded solution at a temperature in the range of
55-60° C. for one (1) hour and then at a temperature in the range
of 45-50° C. for one (1) additional hour. Over a two (2) hour
period thereafter, the slurry is gradually cooled to a temperature in the
range of 15-25° C. and then held at a temperature in the range of
15-25° C. with agitation for at least an additional two (2) hours.
The slurry is filtered, re-slurried with water (285 pbw), filtered again
and washed with isopropanol (78.8 pbw) to produce an aripiprazole wet
cake.

[0024]One portion of an aripiprazole wet cake (20 g), prepared in
accordance with the above-described procedure, was placed in a drying
oven, the oven maintained at a temperature between 60 to 65° C.,
and under a vacuum of 22 inches Hg for a period of 40 hours. A dish of
phosphorous pentoxide (dessicant) also was placed in the oven.
Periodically, approximately a one (1) gram sample of the aripiprazole wet
cake was removed from the oven and analyzed for moisture content by the
volumetric Karl Fischer titration method and also for its hygroscopicity.
At the end of the 40 hour period, the moisture content of the final
sample was analyzed using the coulometric Karl Fischer titration method
and the hygroscopicity of the sample also was determined. The final
moisture content and hygroscopicity values are reported in the Table
below.

[0025]Another portion of the aripiprazole wet cake (20 g), prepared in
accordance with the above-described procedure, was placed in a drying
oven, the oven maintained at a temperature between 70 to 80° C.,
and under a vacuum of 22 inches Hg for a period of 40 hours. A dish of
phosphorous pentoxide (dessicant) also was placed in the oven to
facilitate drying. Periodically, approximately a one (1) gram sample of
the aripiprazole wet cake was removed from the oven and analyzed for
moisture content by the volumetric Karl Fischer titration method and also
for its hygroscopicity. At the end of the 40 hours, the moisture content
of the final sample was analyzed using the coulometric Karl Fischer
titration method and the hygroscopicity of the sample also was
determined. The final moisture content and hygroscopicity values are
reported in the Table below.

[0026]As shown, the samples have the hygroscopicity of Type I anhydrous
aripiprazole.

[0027]XRD data for the anhydrous aripiprazole Batches 1, 2 and 3 produced
at the two drying conditions are provided in FIGS. 1 through 6.

[0028]The present invention has been described with reference to specific
embodiments. However, this application is intended to cover those changes
and substitutions that may be made by those skilled in the art without
departing from the spirit and the scope of the invention. Unless
otherwise specifically indicated, all percentages are by weight.
Throughout the specification and in the claims the term "about" is
intended to encompass + or -5% and preferably is only about + or -2%.